Obsessive-compulsive disorder (OCD) is prevalent and severe, affecting approximately 2% of the population worldwide and producing substantial morbidity even when optimally treated. Serotonin reuptake inhibitors (SRIs) form the mainstay of pharmacotherapy for the disorder; serotonin agonists can exacerbate symptoms; and genetic studies suggest that abnormalities in the serotonin system may contribute to the disorder. However, the nature of any disruption in serotoninergic modulation in OCD remains poorly understood. The 5-HT1B receptor may play a critical role in this regard: the 5-HT1B/1D agonist sumatriptan has been shown to exacerbate OCD symptoms in several studies; and a number of genetic investigations have provided suggestive evidence that a polymorphism in the 5-HT1B gene is associated with OCD risk. 5-HT1B agonists disrupt prepulse inhibition (PPI), a measure of sensorimotor gating that is attenuated in OCD (as well as in several other neuropsychiatric conditions), in animals; and this disruption is ameliorated by chronic treatment with SSRIs - which is standard treatment for OCD. We hypothesize that functional abnormalities of the 5-HT1B receptor contribute to OCD. Measurement of this receptor in vivo in humans has been impossible until very recently, with the development and characterization at Yale of a novel positron emission tomography (PET) ligand, [11C] P943, with nanomolar affinity and good specificity for the 5-HT1B receptor. We propose to image 5-HT1B receptors by [11C] P943 PET in 15 medication-free, non-depressed OCD patients and 15 matched controls. This PET investigation will be enhanced by linking it to two OCD-relevant functional measures. First, we will assess symptom severity in all patients, using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The Y-BOCS was developed in our clinic in the 1980s and remains the gold-standard instrument for rating OCD symptoms. Second, we will assess PPI in all patients and controls. PPI has been shown to be blunted in patients with OCD. While it is not specific - it is also blunted in Tourette syndrome and schizophrenia, among other conditions - it is unique among candidate OCD endophenotypes in that it has been shown, in studies in animals, to be impaired by 5-HT1B agonists. This leads us to hypothesize that 5-HT1B receptor abnormalties may be linked to both OCD symptomatology and to blunted PPI; we expect PPI to correlate negatively with 5- HT1B binding potential. By investigating the 5-HT1B receptor in vivo in humans with OCD and seeking to correlate it with functional measures, we believe that this study will provide important new insight into the dysregulation of serotoninergic neurotransmission in this disorder. This investigation will thereby inform neurobiological models of this prevalent disorder. Through such advances, new treatments can be developed to aid the substantial minority of patients who receive little benefit from existing therapies. PUBLIC HEALTH RELEVANCE: Obsessive-compulsive disorder (OCD) is common and leads to profound suffering; it can be treated with medications that target serotonin, but many patients get little benefit from this or other established treatments. We will examine a particular brain receptor for serotonin, the 5-HT1B receptor, in the brains of patients with OCD, using positron emission tomography. Better understanding of abnormalities in the serotonin system in OCD will pave the way for new pharmacological treatments of this severe neuropsychiatric disorder.